DESCRIPTION (Adapted from Principal Investigator's Abstract): The prevalence of alcohol coadministration with cocaine is very high. It is estimated that 60-80% of cocaine users consume alcohol simultaneously. This drug combination has been identified as the most prominent substance abuse pattern found among individuals presenting to the emergency rooms with substance abuse problems. Alcohol coadministration can significantly alter cocaine pharmacokinetics leading to higher cocaine plasma and brain concentrations, in addition to the formation of the pharmacologically active metabolite, cocaethylene. These pharmacokinetic changes can potentiate cocaine pharmacological effects after administration of this drug combination. The proposed research is designed to examine the effect of coadministration of different doses of alcohol on the disposition rate and the metabolic profile of cocaine, and how the changes in cocaine disposition are reflected on the resulting pharmacological effects. The factors that affect the interaction between cocaine and alcohol, including cocaine dose and repeated exposure to alcohol, cocaine, or both, and how these factors influence cocaine pharmacological effects will be investigated. Also, the factors that affect cocaethylene formation, and the contribution of this metabolite to the pharmacological effects after administration of this combination will be studied. Furthermore, the relationship between the plasma and brain concentrations of cocaine and its metatbolites, and the produced pharmacological effects during the different dosage regimens under investigation will be determined. The information obtained from this research project will be very useful in determining if the changes in cocaine pharmacokinetics, due to alcohol coadministration, and the formation of cocaethylene are responsible, at least partially, for the observed cocaine pharmacological effects after administration of this drug combination. The results may also enable the investigators to identify specific factors that can significantly influence the interaction between cocaine and alcohol and may be responsible for the lethal or near-lethal complications associated with this pattern of abuse. The result of the proposed research could add to our knowledge of how this combination of drugs interact to produce its pharmacological and toxicological effects.